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PhD Studentship: Mitochondrial phenotyping in Alzheimer's Disease

Employer
Global Academy Jobs
Location
United Kingdom
Closing date
Jan 24, 2018

Job Details

Details

Alzheimer’s Disease (AD) is the leading cause of dementia and is characterised by the build-up of amyloid plaques and neurofibrillary tangles (NFT) with a loss of neurons later in the disease course. However, mounting evidence from post mortem and amyloid PET studies indicate that amyloid plaques, in particular do not correlate well with dementia, with overlap in burdens of pathology between individuals with and without dementia. Most cases of AD are sporadic with no identifiable cause and only a small percentage of cases can be attributed to mutations in identified genes. Much work has been done trying to elucidate the mechanisms which cause AD with a view to finding therapeutic targets to slow or stop the progression of AD.

Mitochondrial dysfunction has been indicated in familial and sporadic forms of AD (sAD), with evidence from post mortem and peripheral patient tissue as well as animal models. Mitochondrial enzymatic failure, reduced glucose metabolism and increased reactive oxygen species production have all been shown to occur before amyloid pathology. It is not only mitochondrial function which is altered in sAD; of particular importance in neurons is mitochondrial dynamics. Mitochondria are in a constant state of flux undergoing fission and fusion events allowing them to adapt and meet local energy requirements. Evidence from both neurons and patient fibroblasts show mitochondria are more elongated and have altered distribution throughout the cell. In particular mitochondria are localised around the perinuclear region in sAD fibroblasts suggesting a collapse of the mitochondrial network.

We have access to patient cells from a clinical well characterised AD patient cohort.

The PhD project involves investigating in detail the mechanism by which mitochondria become defective in AD. Concentrating on three areas: mitochondrial dynamics, fission/fusion machinery at mRNA, protein level as well as external manipulations; TSPO expression and modulation in response to stress; substrate utilisation by the mitochondria to generate energy. The project will involve complex biochemical studies using the Seahorse XF analyser and Biolog Omnilog to understand which substrates the AD patient cells can use to successfully to generate energy under different stress conditions as well as correlating this to the mitochondrial dynamics network and cellular distribution. TSPO is a major regulator of cholesterol into the mitochondria and is a major component of the outer mitochondrial membrane. It is currently used a biomarker to assess stress in AD living patients; therefore linking TSPO modulation to mitochondrial abnormalities in patient derived cells will enable a link to the clinic. This project will use patient derived fibroblasts and neurons which have been generated from these fibroblasts using induced neuronal progenitor cell technology. All are already available in the laboratories of the supervisors as are the main methodologies.

 

Funding Notes

The Faculty Scholarships for Medicine, Dentistry & Health cover fees and stipend at Home/EU level. Overseas students may apply but will need to fund the fee differential between Home and Overseas rate from another source.

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Global Academy Jobs works with over 250 universities worldwide to promote academic mobility and international research collaboration. Global problems need international solutions. Our jobs board and emails reach the academics and researchers who can help.

"The globalisation of higher education continues apace, driving in turn the ongoing development of the global knowledge economy, striving for solutions to the world’s problems and educating a next generation of leaders and contributors."

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